Project Summary/Abstract Approximately 20% of patients with recurring seizures have focal drug-resistant epilepsy. It remains challenging to localize the epileptogenic zone (EZ), defined as the region of brain that must be resected or modulated to obtain seizure freedom. No precise localization for the EZ is currently available, and the seizure onset zone remains the gold standard for defining the EZ. Low Frequency EEG Activity (LFA) is relatively understudied and prior data suggests that LFA can improve EZ localization. This proposal?s objective is to fully evaluate the potential of LFA for EZ localization and to clarify pathophysiologic mechanisms that underlie LFA. To this end, a retrospective analysis of 94 patients will examine the potentially efficacy of LFA for estimating the EZ, and a cohort of 40 patients will be prospectively enrolled for more detailed assessments. Clinical outcomes from treated patients will be used to retrospectively determine the EZ, which can be used to evaluate the EZ as estimated by LFA. Prospective patients will receive simultaneous recordings from clinical EEG macroelectrodes as well as from research-grade microelectrodes, which record neuronal units using DC- capable amplifiers. In addition, cutting edge techniques for magnetic resonance spectroscopy will be used to determine neurotransmitter levels for these same brain regions. Finally, non-invasive high density EEG in conjunction with invasive EEG will be used to assess the potential for non-invasive estimation of the EZ. We expect that this proposal will lead to more accurate non-invasive and invasive localization of the EZ, which would lead to improved patient outcomes. Understanding the mechanisms underlying LFA will improve biomarker development and application to clinical use and could influence treatment-related decisions. An informative EEG biomarker based on LFA from non-invasive evaluations means patients could potentially avoid invasive EEG monitoring. For this mentored award, the career plan includes the overall goal of independence as a clinician investigator studying epilepsy with the following training objectives: (1) learn about study design for human research, (2) obtain formal instruction in informatics and biostatistics, (3) understand biomarker development, (4) learn about microelectrode recordings and MR spectroscopy, (5) improve grant writing skills, (6) develop relationships with extramural researchers, and (7) maintain and improve awareness of current literature. The environment for career development includes a multidisciplinary team including epilepsy, neuroradiology, and biostatistics with prior lab experience and support in microelectrode recordings and EEG biomarker development.